title: Polymeric micelles containing reversibly phospholipid-modified anti-survivin siRNA: a promising strategy to overcome drug resistance in cancer.
abstract: The discovery that survivin, a small anti-apoptotic protein, is involved in chemoresistance, opens a new scenario to overcome the drug resistance in cancer. It was shown that siRNA can efficiently inhibit the expression of survivin in cancer cells. However, the clinical use of siRNA is still hampered by an unfavorable pharmacokinetic profile. To address this problem, earlier we developed a novel system to deliver siRNA into cancer cells. Namely, we reversibly modified the survivin siRNA with a phosphothioethanol (PE) portion via a reducible disulfide bond and incorporated the resulting siRNA-S-S-PE conjugate into nanosized polyethyelene glycol 2000-phosphatidyl ethanolamine (PEG2000-PE)-based polymeric micelles (PM), obtaining survivin siRNA PM. The activity of these nanopreparations was evaluated by survivin protein down-regulation, tumor cell growth inhibition, and chemosensitization of the treated tumor cells to paclitaxel (PXL). We found a significant decrease of cell viability and down-regulation of survivin protein levels after treatment with survivin siRNA PM in several cancer cell lines. In addition, the down-regulation of survivin by treating cells with survivin siRNA PM, elicited a significant sensitization of the cells to PXL, in both sensitive and resistant cancer cell lines. Finally, we demonstrated successful co-delivery of PXL and survivin siRNA in the same PM leading to superior therapeutic activity compared to their sequential administration. Our results support the use of this new platform for the treatment of the most aggressive tumors.
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Salzano
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Riehle
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Navarro
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Perche
authors.affiliation: Department of Pharmacy, University of Naples, Federico II, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: De Rosa
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA. Electronic address: v.torchilin@neu.edu.
authors.forename: V P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D004337:Drug Carriers / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008823:Micelles; D009369:Neoplasms / Q000628:therapy; D017239:Paclitaxel / Q000494:pharmacology; D010743:Phospholipids / Q000737:chemistry; D034741:RNA, Small Interfering / Q000494:pharmacology*; D000077022:Survivin; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D004337:Drug Carriers; D051034:Inhibitor of Apoptosis Proteins; D008823:Micelles; D010743:Phospholipids; D034741:RNA, Small Interfering; D000077022:Survivin; D017239:Paclitaxel
keywords: Co-delivery; Multidrug resistance; Paclitaxel; Polymeric micelles; Survivin siRNA